Abstract Bariatric surgery is increasingly recognized as a potent tool for the treatment of type 2 diabetes (T2D), yielding not only weight loss but also rapid improvements in glycemia allowing discontinuation of diabetes-related medication within days after surgery1. However, along with this metabolic success comes an increased incidence of severe hypoglycemia (termed post-bariatric hypoglycemia; PBH) for a subset of patients. Severe hypoglycemia causes not only distressing adrenergic and cholinergic symptoms but also neuroglycopenia and hypoglycemia unawareness, impairing safety and increasing risk for disability, syncope, arrhythmias, seizures, coma, and death. Although initially thought to occur in <1% of patients and isolated to roux-en-Y gastric bypass (RYGB), latest estimates suggest that it occurs in ~30% of patients, after both RYGB and vertical sleeve gastrectomy (SG), with similar presentation and spectrum of severity. Increased postprandial incretin and insulin secretion, increased insulin sensitivity, and altered bile acid metabolism have all been implicated in the pathogenesis of PBH. Recent work also suggests that RYGB reduces counterregulatory responses to hypoglycemia. Together, these data suggest that, like the mechanisms that underlie the metabolic success of surgery, the mechanism(s) that underlie PBH are multi-factorial. However, an important feature of PBH is the timing of symptoms. While increases in incretins and improvements in glucose homeostasis occur almost immediately, the onset of PBH typically occurs years postoperatively. Thus, there is more to PBH than increased incretin and consequently insulin responses. The goal of this proposal is to utilize a combination of preclinical and clinical studies to identify physiological and molecular mechanisms that underlie PBH, to determine whether these changes also contribute to surgery-induced improvements in glucose homeostasis, and to define potential therapeutic interventions for PBH. We will determine if decreases in the counterregulatory hormonal responses to hypoglycemia precede bariatric surgery-induced improvements in peripheral insulin sensitivity in rodents (Aim 1). We will test the hypothesis that counterregulatory hormonal responses to hypoglycemia are impaired in post-bariatric patients with or without PBH (Aim 2). Finally, we see that FGF19 is increased in patients with PBH and we will utilize both clinical and preclinical strategies to answer the critical questions of what drives this increase in FGF19 (Aim 3) and whether it is required for the development of PBH (Aim 4).